Metronidazole therapy in mice infected with tuberculosis

Abstract

The capacity of metronidazole to inhibit the growth of Mycobacterium tuberculosis was tested in in vitro and in vivo mouse models. In vitro addition of metronidazole to cultures of infected bone marrow-derived macrophages had no effect, nor did it increase the reduction in bacterial load due to isoniazid. In vivo, metronidazole did not reduce bacterial numbers in the lungs of aerosol-infected mice during the active stage of the disease, during a phase of containment, or after prolonged isoniazid therapy (Cornell model). A small but significant reduction was seen if metronidazole therapy was given during an established chronic disease state 100 days after aerosol administration. These data indicate that under most conditions M. tuberculosis organisms are not in a metabolic state in which they are susceptible to the action of metronidazole and, hence, that this drug would be of limited clinical value.

Figures

FIG. 1

Effect of increasing doses of drug on growth of M. tuberculosis Erdman within bone marrow-derived macrophage monolayers. The right panel shows the results of an experiment in which increasing doses of metronidazole were added to a fixed dose of isoniazid (0.75 μg) previously determined to inhibit 99% of the bacterial inoculum. Data are expressed as the mean numbers of bacteria recovered from three separate culture wells; standard errors of the means did not exceed 0.5.

FIG. 2

Failure of metronidazole (15 mg/kg/day) given daily from day 30 through day 80 after aerosol administration to inhibit growth of M. tuberculosis Erdman in the lungs. ■, controls; □, metronidazole therapy. Data indicate mean numbers of bacteria recovered (n = 4); standard errors of the means did not exceed 0.3.

FIG. 3

Capacity of metronidazole (15 mg/kg/day) to inhibit growth of M. tuberculosis Erdman during the chronic stage of disease. Treatment was given from day 100 to day 130, with bacterial numbers assessed on days 115 and 130. Data are mean standard error of the mean numbers of bacteria recovered (n = 4).